Grant: Idea to Innovation

Nucleic acids (NAs) make up the genetic material carrying information for the biological function of living organisms. The safe and effective delivery of nucleic acids (NAs), including DNA and RNA, opens up new routes for the treatment of disease, including gene therapy and vaccines. Although viral particles have been used to deliver NAs both in the lab and in clinical trials, there are possible side-effects associated with viral particles, in addition to a limited payload capacity precluding many applications. Therefore, the development of safe and effective non-viral gene delivery particles has become an intense field of research. Lipid nanoparticles (LNPs) have been used successfully in several gene delivery formulations, including recent RNA-based vaccines against COVID-19. However, polymer nanoparticles (PNPs) offer several potential advantages over LNPs, including stability, ease of functionalization, and variability of properties, promoting research into PNPs for next-generation gene delivery. In this grant we describe the development of a new type of gene delivery PNP, termed a "polyplex-in-hydrophobic-core" (PIHC) micelle in which the NA cargo is surrounded by a condensed hydrophobic polymer core which itself is surrounded by a hydrophilic polymer shell. This structure provides enhanced protection of NAs against attack and degradation by enzymes in the bloodstream, along with minimizing exposure of healthy cells to potentially harmful charged polymers. These features make PIHC micelles potentially safer and more effective vectors for vaccines and other gene-based medicines compared to LNPs and other PNPs.